As a class, triazoles have shown a wide range of utility, particularly in the formulation of antifungal drugs for treating mammalian afflictions including, for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, and posaconazole as well as antifungal compositions for agricultural applications including, for example, epoxiconazole, triadimenol, propiconazole, metconazole, cyproconazole, tebuconazole, flusilazole and paclobutrazol.
Prior art references disclose several diazotization procedures for preparing such compounds. Generally, an amine is reacted with nitrous acid, which is generated by the addition of a mineral acid or an organic acid. Most commonly, an excess of sulfuric, hydrochloric, or acetic acid is used to generate in situ the nitrous acid used in the diazotization reactions. This acidic medium must be disposed of or stored once the reaction is complete. These reactions are maintained at temperatures typically ranging from 0° C. to 50° C. In the case of triazole synthesis, filtration and drying or distillation steps are typically required in order to isolate the target triazole(s) before dissolving the triazole product(s) in either a basic aqueous solution or a highly acidic aqueous solution. These additional steps can prove both costly and time consuming in terms of manufacturing.
It is an object of the present invention to provide improved methods for the diazotization of amines capable of producing a range of triazole compounds that can be used as final products or as intermediates in more complex synthesis processes that is both simplifies the synthesis operation and avoids the use of strong acids.
It is another object of this invention to provide methods for the direct synthesis of triazole compounds of sufficient purity and concentration directly in an aqueous solution and thereby reduce or eliminate the need for subsequent isolation, concentration, neutralization and/or purification procedures, thereby both reducing the complexity of the process and reducing or eliminating the need to dispose of any related aqueous or organic waste.
Additionally, it is an object of this invention to provide methods using carbon dioxide and water to form carbonic acid in concentrations sufficient to result in the formation of nitrous acid.
These and other objects of the present invention are accomplished by the methods and examples detailed below in which appropriate amine(s), nitrite salt(s) and carbon dioxide are dissolved in an aqueous reaction solution and reacted to produce the target triazole(s).
Those of ordinary skill in the art will appreciate that BZT is widely used as a copper and/or yellow metal corrosion inhibitor, as an intermediate or primary compound in the synthesis of dyes, fungicides and plant growth regulators, and as a polymerization catalyst. Consequently, a number of BZT synthesis procedures have been developed over the years, typically involving a diazotization reaction in which a nitrite salt, typically orthophenylenediamine (OPD), and an acid are mixed in an aqueous system and allowed to react for a substantial period of time. Certain of these synthesis procedures have been the subject of previous U.S. Patents including, for example, U.S. Pat. Nos. 2,861,078; 3,227,726; 3,334,054; 3,564,001 and 4,299,965, the contents of which are incorporated, in their entirety, by reference.
In many instances, however, the product(s) of these synthesis procedures are impure and/or of lesser quality than desired. Accordingly, in many instances the initial BZT product must be subjected to additional processing including, for example, further processing by carbon treatment, crystallization and/or distillation processing steps, thereby increasing both the time and expense of preparing a suitable BZT composition. In addition, certain of these methods are typically run at relatively low solids concentrations and can, for example, result in an initial product that has a relatively low BZT content of, for example, less than 15% in the final reaction mixture.
Accordingly, it is an object of the present invention to provide a method for the preparation of BZT and other triazoles and their derivatives that is less expensive, relatively simple, more ecologically friendly than those presently available capable of producing sufficiently pure triazole product(s) whereby additional purification steps are not required.
As disclosed in U.S. Pat. No. 4,299,965, for example, an aqueous mixture of orthophenylenediamine and acetic acid is slowly added to a cooled sodium nitrite solution after which the reaction represented below in Formula [1] is allowed to proceed for a period of about one to three hours. The reaction mixture will have a concentration of from about 12 wt % to 22 wt % of active ingredients. It is suggested that the order in which the reagents is added is not important, so long as one reagent is being added to the other at a rate sufficiently so as to keep the temperature of the reaction mixture below about 25° C.

The reaction step is then followed by neutralization step using sodium hydroxide to increase the pH of the reaction mixture to 6 to 6.5, with the reaction and neutralization steps being achieved at relatively low temperatures, typically between 5° C. and 25° C. A precipitate of BZT is formed, filtered and washed with cold water to yield technical grade product suitable for use in industrial applications. The relative aqueous concentrations of the reactants is preferably adjusted to give 15 to 25 wt % of the BZT product, a mole ratio of 0.9 to 1.1 for orthophenylenediamine to sodium nitrite and a mole ratio of 1.8 to 2.2 for acetic acid to orthophenylenediamine. The amount of caustic used in the neutralization must be less than about 0.8 moles per mole of acetic acid.
Similar prior art synthesis methods have used other strong acids including, for example, sulfuric acid, to achieve a result similar to that obtained with the acetic acid. The reactions utilized in other methods of synthesizing BZT are illustrated below in general Formula [2] and example Formulae [3]-[5].
